Activation of cytotoxic lymphocytes is a complex and poorly understood process. Two immunosuppressive drugs, Cyclosporin A (CsA) and Hydrocortisone (Hy) were examined in parallel for their effect on the generation of cytolytic lymphocytes. Peripheral blood lymphocytes (PBL) were stimulated with allogeneic cells to produce allospecific CTL, or with purifed recombinant IL-2 (R IL-2) to activate lymphokine-activated killer cells (LAK). Both CTL and LAK activity were measured in a 4-hour chromium release assay after 7 days of activation. Lysis by CTL was tested against stimulator PBL (not blasts) and LAK against fresh sarcoma tumor cells. At pharmacologic doses, CsA inhibited only CTL generation, while Hy inhibited only LAK. LAK activation is believed to occur by interaction of IL-2 with the precursor cell, via a non receptor mediated interaction. We are attempting to define the exact means of interaction, and then pursue the early events leading to the expression of cytotoxic activity.